We propose to develop F-18 labeled agents targeting _-amyloid (A_) aggregates for positron emission tomography (PET) imaging of patients with Alzheimer's disease (AD). AD is a common neurodegenerative disease of the brain with a high prevalence in the older population. It is believed that AD is associated with the overproduction and buildup of soluble A_ peptides and insoluble A_ aggregates in the brain. The accumulation of A_ plaques in the brain is thought to be a key risk factor for the pathogenesis of this disease. Currently, there is no imaging method to diagnose AD. Only postmortem biopsy and color staining of the brain tissues for A_ aggregates in senile plaques can definitively diagnose the disease. Therefore, it is extremely important to develop in vivo PET imaging agents for A_ plaques which can be used as biomarkers in the diagnosis and treatment of AD. In the past funding period, we have developed several potent F-18 labeled stilbene derivatives, which show desirable in vitro and in vivo properties as PET imaging agents. In the next funding period, we propose to test additional F-18 labeled biphenyl acetylene and phenyl-naphthalene derivatives. These proposed new agents may have enhanced in vitro and in vivo stability and higher brain uptake as well as better selective localization of A_ plaques in the brain. To accomplish these objectives we will: 1. synthesize the proposed new ligands 2. perform in vitro binding studies using AD brain homogenates to select ligands with good binding affinity (Ki <10 nM). 3. perform 18F labeling studies and test the in vitro stability. 4. study the biodistribution in normal mice (brain uptake >4 %dose/g, at 2 minutes after an iv injection). 5. perform in vitro autoradiography studies using postmortem AD brain sections (to show high and selective A_ plaque-labeling). Ultimately, preferred candidates will be tested in normal non-human primates by positron emission computed tomography (PET) imaging. From this series of novel 18F labeled compounds targeting A_ plaques, one or two final candidates will be selected as PET imaging agents for testing in humans, through which the A_ burden relating to pathological states of AD may be measured. The PET imaging of A_ plaques may be critically useful for the early detection of senile plaques in patients with AD and the monitoring of patients undergoing drug treatment designed to reverse the buildup of A_ plaques in the brain.